The use of radioactive materials in diagnostic medicine has been readily accepted because these procedures are safe, minimally invasive, cost effective, and they provide unique structural and/or functional information that is otherwise unavailable to the clinician. The utility of nuclear medicine is reflected by the more than 13 million diagnostic procedures that are performed each year in the U.S. alone, which translates to approximately one of every four admitted hospital patients receiving a nuclear medical procedure. [Adelstein et al. Eds. Isotopes for Medicine and the Life Sciences; National Academy Press: Washington, D.C., 1995; Wagner et al., “Expert Panel: Forecast Future Demand for Medical Isotopes,” Department of Energy, Office of Nuclear Energy, Science, and Technology, 1999; Bond et al., Industrial and Engineering Chemistry Research 2000, 39, 3130-3134.]
The use of radiation in disease treatment has long been practiced, with the mainstay external beam radiation therapy now giving way to more targeted delivery mechanisms including sealed-source implants containing palladium-103 or iodine-125 that are employed in the brachytherapeutic treatment of prostate cancer and samarium-153 or rhenium-188 that are conjugated to diphosphonate-based biolocalization agents that concentrate at metastasis in the palliation of bone cancer pain. More recently, the U.S. Food and Drug Administration (FDA) has approved use of the first radioimmunotherapy (RIT) drug that relies on radionuclide conjugation to peptides, proteins, or antibodies to selectively concentrate at the disease site whereby radioactive decay imparts cytotoxic effects. Radioimmunotherapy represents the most selective means of delivering a cytotoxic dose of radiation to diseased cells while sparing healthy tissue, [Geerlings et al., Akzo Nobel, N. V.: US, 1993; Whitlock et al., Industrial and Engineering Chemistry Research 2000, 39, 3135–3139; Imam, Int. J. Radiation Oncology Biol. Phys. 2001, 51, 271–278; Hassfjell et al., Chemical Reviews 2001, 101, 2019-2036; McDevitt et al., Science 2001, 294, 1537–1540] and the plethora of information about disease genesis and function arising from the human genome project and proteomics technologies is expected to propel RIT into a leading treatment for micrometastatic carcinoma (e.g., lymphomas and leukemias) and small- to medium-sized tumors.
Because of their use in medical procedures, various governing bodies (e.g., the U.S. FDA) mandate rigorous purity requirements for radiopharmaceuticals. Regulations governing the use of radionuclides for therapeutic applications are even more stringent, and such strict regulation is warranted given the greater potential harm posed by long-lived high linear energy transfer (LET) radionuclidic impurities. Manufacturers that can ensure the production of therapeutically useful radionuclides with the following three characteristics will be at a significant advantage entering the FDA review process and, subsequently, in the deployment of their products in the medical technology markets:                (1) High radionuclidic purity;        (2) High chemical purity; and        (3) Predictable purification methods and reliable production schedules.        
The need to ensure high radionuclidic purity stems directly from the hazards associated with the introduction of long-lived or high energy radioactive impurities into a patient, especially if the biolocalization and body clearance characteristics of the radioactive impurities are unknown. Radionuclidic impurities pose the greatest threat to patient welfare, and such contaminants are the primary focus of clinical quality control measures that attempt to prevent the administration of harmful, and potentially fatal, doses of radiation to the patient.
Chemical purity is vital to a safe and efficient medical procedure because the radionuclide must generally be conjugated to a biolocalization agent prior to use. This conjugation reaction relies on the principles of coordination chemistry wherein a cationic radionuclide is chelated to a ligand that is covalently attached to a biolocalization agent. In a chemically impure sample, the presence of ionic interferents can inhibit formation of the radioimmunoconjugate resulting in a substantial quantity of radionuclide not bound to the biolocalization agent. Therapeutic radionuclides not associated with a biolocalization agent not only pose a health concern if administered, but represent an inefficient use of both the radionuclide and the costly biolocalization agent.
Candidate radionuclides for RIT typically have coordination chemistry that permits attachment to various biolocalization agents, radioactive half-lives in the range of 30 minutes to several days, a convenient generator or nucleosynthesis-based production route, and a comparatively high LET. The LET is defined as the energy deposited in matter per unit path length of a charged particle, [Choppin, et al., J. Nuclear Chemistry: Theory and Applications; Pergamon Press: Oxford, 1980] and the LET of α-particles is substantially greater than β−-particles. By example, α-particles having a mean energy in the 5–9 MeV range typically expend their energy within about 50–90 μm in tissue, which corresponds to several cell diameters. The lower LET β−-particles having energies of about 0.5–2.5 MeV may travel up to 10,000 μm in tissue, and the lower LET requires as many as 100,000 β−-emissions at the cell surface to afford a 99.99% cell-kill probability. For a single α-particle at the cellular surface, however, the considerably higher LET provides a 20–40 percent probability of inducing cytotoxicity as the lone α-particle traverses the nucleus. [Hassfjell et al., Chemical Reviews 2001, 101, 2019–2036.]
Bismuth-213 is the most attractive candidate for α-particle RIT, but its supply chain is in need of optimization. Uranium-233 is the longest lived radionuclidic parent of 213Bi, and it was this fissile isotope of uranium that was synthesized by neutron irradiation of thorium-232 for defense purposes. During neutron irradiation of 232Th, however, competing nuclear reactions yielded small quantities of uranium-232 (232U). The 232U contaminant is problematic for two principal reasons:                (1) Decay of 232U leads to gaseous radon-220 with a 55.6 second half-life, which can migrate during processing and raises contamination concerns; and        (2) Decay of 232U also leads to thallium-208 that has a high energy (2.6 MeV) γ emission that cannot be effectively shielded; thus, exposing both the patient and the clinical personnel to undesirable and potentially harmful radiation.        
The most feasible means of obtaining pure 213Bi from 229Th containing trace contaminants of thorium-228 (228Th) is to selectively isolate 225Ac. Current processing schemes adopt a linear multi-step approach in which 225Ra and 225Ac (and the radium-224 contaminant) are eluted in concentrated nitric acid from an anion-exchange column that retains both 229Th and 228Th. A subsequent separation of 225Ac from 225Ra and 224Ra is performed prior to deposition of the 225Ac on a support material for generator shipment. The retention of macroconcentrations of Th(IV) on anion-exchange resins is cumbersome and inefficient as the Th(IV) must be regularly eluted from the large anion-exchange columns to minimize radiolytic degradation. Inefficient elution at this stage results in losses of the precious 229Th source material.
The same LET that makes α- and β−-emitting nuclides potent cytotoxic agents for cancer therapy also introduces many unique challenges into the production and purification of these radionuclides for use in medical applications. In fact, a major hurdle currently limiting the use of α-particles in RIT stems primarily from issues of availability.
The most convenient source of the 213Bi precursor 225Ac is 229Th, which can be gleaned from 233U stockpiles previously amassed by the U.S. government. The purified 229Th can then be used as an cc-particle source material for RIT. Thus, the vital aspects of the production of 225Ac include preservation of the 229Th parent source material, efficient recovery and use of the 225Ra parent of 225Ac, and the chemical isolation of 225Ac that breaks the 224Ra decay chain leading to highly undesirable radionuclidic contaminants.
As discussed above, the use of high LET α-emitting radiation holds great promise for the therapy of micrometastatic carcinoma, but realization of the full potential of targeted radiotherapy requires the development of ample supplies and reliable generators for high LET radionuclides. [Geerlings et al., Akzo Nobel, N. V.: U.S. Pat. No. 5,246,691, 1993; Whitlock et al., Industrial and Engineering Chemistry Research 2000, 39, 3135–3139; Imam, Int. J. Radiation Oncology Biol. Phys. 2001, 51, 271–278; Hassfjell et al., Chemical Reviews 2001, 101, 2019–2036; McDevitt et al., Science 2001, 294, 1537–1540] One candidate α-emitter proposed for use in cancer therapy is 213Bi [Geerlings et al., Akzo Nobel, N. V.: U.S. Pat. No. 5,246,691, 1993; Imam, Int. J. Radiation Oncology Biol. Phys. 2001, 51, 271–278; Hassfjell et al., Chemical Reviews 2001, 101, 2019-2036] which forms as part of the 233U decay chain.
Bismuth-213 has recently been obtained for use by elution from a conventional generator in which the relatively long-lived (i.e., 10.0 day) 225Ac parent is retained on an organic cation-exchange resin while the 213Bi is eluted with HCl [Hassfjell et al., Chemical Reviews 2001, 101, 2019–2036; Lambrecht et al., Radiochimica Acta 1997, 77, 103–123; Mirzadeh, Applied Radiation and Isotopes 1998, 49, 345–349] or mixtures of Cl− and I−. [Hassfjell et al., Chemical Reviews 2001, 101, 2019–2036; Lambrecht et al., Radiochimica Acta 1997, 77, 103–123; Mirzadeh, Applied Radiation and Isotopes 1998, 49, 345–349; Geerlings; Akzo Nobel, N. V.: U.S. Pat. No. 5,641,471, 1997; Geerlings; Akzo Nobel, N. V.: U.S. Pat. No. 6,127,527, 2000.] This generator strategy suffers from the adverse effects of radiolytic degradation of the support material that leads to low yields of impure 213Bi and to erratic generator behavior. In order for 213Bi to be successfully deployed in cancer therapy, a new generator technology must be developed.
The multicolumn selectivity inversion generator (MSIG) described in application Serial No. 60/372,327 filed Apr. 12, 2002 is capable of reliably producing near theoretical yields of 213Bi of exceptionally high radionuclidic and chemical purity. By minimizing the adverse effects of radiolytic degradation of the support material, this 213Bi generator operates at predictably high efficiency over the entire duty cycle. In addition to exceeding the vital purity criteria, the purified 213Bi product is delivered in a small volume of NaCl/(Na,H)OAc buffer solution at pH=4.0, which is seamlessly integrated into the radioconjugation reaction involving the biolocalization agent. The operational simplicity of the multicolumn selectivity inversion generator for the production-scale purification of 213Bi is ideally suited to automation, which is more efficient and reduces the probability of human error to ensure that more patients can be safely treated with 213Bi α-particle immunotherapy. Because this 213Bi generator technology is downstream from 225Ac production and purification, the product emerging from the 225Ac purification method under development should be compatible with this 213Bi generator technology. The input medium for the 213Bi generator is 0.10 M HCl, which places a restriction on the output from the 225Ac purification process. One restriction, by example, would be that use of an acidic extraction reagent could not immediately precede the 225Ac purification process, as 225Ac would be most conveniently stripped from such a reagent using high concentrations (i.e., greater than 1 M) of a strong acid. Thus, overall integration of the separations processes into the global 213Bi production flowsheet is an important facet of the design of a new 225Ac purification technology.
An ideal 225Ac production technology should offer operational simplicity and convenience as well as reliable production of near theoretical yields of the desired 225Ac radionuclide, preferably having high chemical and radionuclidic purity. Current production methods of 225Ac are poorly suited, however, to systems involving macroconcentrations of radionuclidic parents and the high LET radionuclides useful in therapeutic nuclear medicine also can damage the separations media.